Until recently, studies attempting to identify viral pathogens were restricted to testing for previously known viruses detectable by cell culture, PCR, staining with antigen-specific antibodies, or through sero-conversion. Testing was therefore restricted to already characterized viruses, largely those that had been discovered through their cytopathic effects on cells grown in vitro. The introduction of high-throughput DNA sequencing now allows metagenomic approaches to identify all the viruses present and has revealed a large number of previously unknown viruses, belonging to many different viral families, particularly in the feces of humans as well as in wild and domesticated animals. The very high sensitivity of nucleic acid testing has also revealed a high rate of enteric viral infections not just in diarrheic but also in healthy humans and animals. Here a metagenomics/bioinformatics approach will be used to first generate a comprehensive list of all the enteric viruses present in a large cohort of rhesus macaques with idiopathic chronic diarrhea (ICD), a common inflammatory condition of the colon resembling human ulcerative colitis. In order to identify candidate viral pathogens associated with this unexplained disease, a classic case control study will compare the presence and viral concentration of all the virus present in a large number of animals with ICD versus healthy controls. Viral replication of these viruses in the anatomical site of tissue pathology in animals affected with ICD will then be tested using in situ hybridization. The top candidate viral pathogens, most strongly associated with ICD in the largest number of animals, will then be orally inoculated into juvenile macaques and the development of ICD, viral shedding, and viral replication in the colon closely monitored. We will therefore apply the power of metagenomics and bioinformatics tools combined with a classic epidemiological study for an all-inclusive test of the role of viruses in a common and chronic primate disease affecting rhesus macaque research colonies. A large numbers of animal samples will be carefully selected by veterinary science experts and their viral nucleic acids comprehensively analyzed followed by animal inoculations to identify one or more viral pathogens. This study will also advance our understanding of viral diversity in a large primate population, and demonstrate the utility of metagenomics to identify all viruses present for subsequent disease association studies comparing viral replication in affected cases versus healthy controls. The identification of virus(es) causing ICD will not only assist managing the health of the non-human primate species most often used in biomedical research but will also provide model systems for virally induced chronic diarrhea/colitis and viral targets for vaccine development to control a major source of mortality and animal variability in primate centers.